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MICR 3330 Midterm > Lecture 8 > Flashcards

Lecture 8 Flashcards

1
Q

What supergroup do Flaviviruses represent?

A

Supergroup II of +RNA viruses

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2
Q

Explain the phylogeny of Flaviviridae?

A

Flavivirus: Infect animals & humans: transmission by insect vectors
Hepacivirus: Infect humans, no arthropod vector
Pestivirus: Infect animals, no arthropod vector

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3
Q

How are viruses classified in the Flavivirus genus?

A

Viruses in the Flavivirus genus are transmitted by arthropod vectors
Principal hosts and natural reservoirs: birds, rodents, monkeys, pigs

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4
Q

What are the defining features of Flavivirus?

A 
Envelop protein layer: 180 copies each of E and M proteins (T = 3) 
Lipid Bilayer (envelope)
Nucleocapsid core: icosahderal symmetry (T = 3), 25- 30 nm, CP basic
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5
Q

Explain the genome of Flavivirus’s

A

E proteins (500 aa) lie on top of membrane, smooth surface
Positive strand, ssRNA genomes of 10- 11 kb
A single ORF, poly-protein, proteolytic processing
Many members are transmitted by insect vectors in which they also replicate

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6
Q

What are arboviruses?

A

Viruses of humans and animals that also replicate in arthropods and are transmitted by insect vectors
Members of the genus Flavivirus are transmitted by mosquitos or ticks

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7
Q

Explain the major disease of Yellow fever

A

An ancient and severe disease first recorded in 1648

Carlos Finlay first suggested transmission of yellow fever by mosquito

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8
Q

Which was the 1st human virus discovered?

A

Yellow fever in 1901, W. Reed; transmissible by mosquitos
Still a public health threat in Africa and certain countries in South America
Mortality: 20- 50% in severe epidemics
Hepatitis: affects liver, skin becomes yellow

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9
Q

Why was yellow fever so dangerous?

A

Frequent epidemics in the US 1700s- 1800s (introduced via slave trades)
The Philadelphia epidemic in 1973:
10% of total city population died
Massive exodus further reduces population
Washington fled

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10
Q

Explain the Yellow Fever Commission

A

Established by US congress, charged to find cause and cure for yellow fever
W. Reed: Serum contains the ‘virus’, infectious agent is filterable, mosquito transmits disease

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11
Q

How was yellow fever controlled and prevented?

A

Clearance of mosquitos and vaccination help end yellow fever epidemic in US

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12
Q

How did Max Theiler help control yellow fever?

A

Attenuated vaccine strain 17-D, derived from a natural virulent strain Asibi from West Africa
Initial passages in monkeys, then 100 passages in laboratory mice and embryonic cell cultures
17D provides immunity in monkeys and humans
28 M doses produced

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13
Q

How does 17D for yellow fever change?

A

68 nts, 32 aa, 12 in E protein

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14
Q

Explain West Nile virus

A

Identified (1937) in West Nile, Uganda
Widespread in Africa, South America, Middle East
Infection of CNS, causing encephalitis, paralysis
1999: summer, introduced to Queens, NYC
2000: re-appeared along with mosquito season
2002: blood transfusion and transplant shown to cause new infections in recipient patients
Epidemic in birds & mosquitos in N. America

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15
Q

Explain the transmission cycle of West Nile virus

A

Infected mosquitoes transmit the virus to birds. Birds of some species, get ill and die, while others become infected but do not show signs of the disease

1) Crow to crow transmission
2) Bird transmit to mosquito, and mosquitos become infected when they bite birds infected with West Nile
3) “Dead-end carriers”: virus in mammals is usually not sufficient to be transmitted back to mosquito, ending transmission cycle
4) Mammals bitten by infected mosquitoes ,may test positive for WNV, although some mammals will not get it

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16
Q

Explain the Zika virus and its global spread

A

First isolated in 1947 in Zika Forest, Uganada
Subsequent spread to other equatorial countries
Since 2007, moving across Pacific Ocean to reach America
Zoonotic disease, and human activities are assisting in the spread

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17
Q

What does Zika do to infants?

A

2015-2016 epidemic in Brazil: 1.5 M reported cases, > 3500 cases of microcephaly within 4 months (2015.10 to 2016.01)

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18
Q

What happened in regards to zika in February of 2016?

A

WHO declares Zika as a Public Health Emergency of International Concern

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19
Q

Why is Zika dangerous?

A

Asymptomatic in adults, but affects infants in the mothers womb –> microcephaly: infants, small brains, cognitive delays

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20
Q

Describe Hepatitis C

A

One of the most widespread and severe diseases globally: 170 M people infected; 3-4 M new infections, and 399,000 deaths per year
75-85% of acute infections became chronic, leading to cirrhosis and liver cancer
Lack of effective treatment until very recently

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21
Q

How is Hep C transmitted?

A

Initially the “None A None B (NANB)” hepatitis

Transmission via blood, blood products, organ transplant, injection drug use, body piercing

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22
Q

How was Hep C discovered and how do they screen for Hep C?

A

Discovery in 1989 via molecular cloning

Blood screening for HCV started in Canada (1990), followed by the US (1992)

23
Q

Explain the HCV epidemiology in Egypt, Asia, Australia

A

49-64 M infections among adults in Asia, Egypt, Australia
Egypt: 15% (50% among people born before 1960)
High HCV prevalence due to campaign to treat schistosomiasis (reuse of syringes among children)
Pakistan: 4.7%
Taiwan: 4%

24
Q

Explain the human liver and hepatocytes

A

Source of bile salts
Function in detoxification
Break down bilirubin (comes from drugs, alcohol)
Active in protein synthesis and storage
Highly active metabolism (carbohydrates, lipids)
Hepatocytes have a lifespan of 6 months
Liver can only handle so much can’t handle –> diabetic type II

25
Q

What are some facts and stats about HCV?

A

HCV infects hepatocytes (liver cells) and lymphocytes

50 virions produced per day per hepatocyte –> 10^12 virions produced in a patient every day

26
Q

What are the 7 genotypes for HCV?

A

Genotypes 1-3: America, Europe, Japan (genotype 1 is most prevalent)
Genotypes 3,6: Asia
Genotypes 4,5: Africa
Genotype 7: recently detected in Africa; less clinical significance
Infection with one genotype does not confer immunity against infection by another, due to great genetic divergence between genotypes (30-35%)

27
Q

How is HCV detected?

A

HCV viral RNA by RT-PCR
Enzyme immunoassay (ELISA) to detect HCV antibodies
Chronic HCV infections remain asymptomatic during the first decades

28
Q

What are the long term outcomes of infections with HCV?

A

Out of 100 people infected with Hep C:
75-85 people develop chronic HCV infections, of which:
60-70 people will develop chronic liver disease
5-20 people will develop cirrhosis over a period of 20-30 years
1-5 people die from cirrhosis or liver cancer
Severe outcomes: Cirrhosis, hepatocellular carcinoma, liver failure, death

29
Q

Why is Hep C dangerous?

A

Alcohol consumption, certain prescription drugs increase chance of cirrhosis
Vastly variable, 7 genotypes, low levels of protective immunity, hard to control
Lack of effective experimental systems impeded research & antiviral development until recently

30
Q

What is the treatment for HCV (old and new)?

A

No vaccines available, so treatment relies solely on antiviral drugs
Old treatment: Pegylated interferon (INF) alpha, ribavirin (RBV) –> not many could complete this treatment
New treatment with direct acting antivirals (DAAs)

31
Q

Why is HCV bad for the healthcare system?

A

Large healthcare cost and economic burden:
Average lifetime cost for treatment: $33,000
Costs for single liver transplant: $200,000

32
Q

Why was research for HCV so slow?

A

Prior to 2005: Research and antiviral development for HCV slow due to low viral tiger in the liver, lack of effective experimental systems, relied on full-length and subhenomic replicon and humanized mice (mice liver contained mostly human liver cells)

33
Q

What was the long awaited break in HCV research?

A

Isolate JFH-1, which was obtained from Japanese patient with a rare case of fulminant hepatitis
JFH-1 grows well in cell culture without the need for adaptive mutations
When transferred to human hepatoma cells (Huh-7), JFH-1 produces infectious virions

34
Q

What are some highlights in HCV research:?

A

1989: Identification of HCV
1998: Interferon-a and ribavirin combination therapy (first treatment)
2003: Proof of concept clinical studies of an HCV protease inhibitor and functional HCV psuedoparticles described, working on antiviral drugs

35
Q

What is the importance of the polyprotein in yellow fever?

A

Polyprotein is cleaved by multiple proteases into 10 mature and functional proteins
Signalase: cleaves signal peptide
NS2B/NS3 (serine protease): cleaves between multiple spots
NS5: One protein with 2 domains
NS3: Protease-helicase
C: capsid
prM: prM

36
Q

Explain the genome structures, polyprotein processing and membrane association for HCV?

A 
Polyprotein undergoes IRES mediated translation 
Proteins:
C: Core protein 
E1/E2: Envelope glycoprotein 
p7/NS2: Protease 
NS3: Serine Protease, Helices
A: Cofactor for Serine protease 
NS4B/NSSA: Membranous web 
NSSB: RDRP 
All these proteins are critical for viral replication
37
Q

Explain how the topology of viral proteins work?

A

Intracellular virion: E, prM, heterodimer

Extracellular virion: E dimer, M, prM

38
Q

What are some proteins encoded by the Yellow Fever virus?

A

anchC: anchored capsid protein, precursor to capsid proteins; signal sequence inserted in membrane is cleaved by viral protease
C: capsid protein; encapsidation of viral genome RNA
prM: Precursor to M; binds to E glycoprotein to form a heterodimer, inhibits membrane fusion during transit through Golgi. Cleavage to produce mature M and pr
M: Small envelope glycoprotein. Functions in mature virion is unknown
E: Major envelope glycoprotein. Receptor binding, fusion of viral envelope with cell membrane

39
Q

What are some fo the VRC proteins encoded by the Yellow Fever virus?

A

NS1: Component of replicase, possibly involved in VRC formation
NS2A: Component of replicase; either direct role in replication or targeting VRC to the ER membrane
NS2B: Part of the viral protease that cleaves viral polyprotein
NS3: Viral serine protease (at N-terminal domain) involved in polyprotein cleavage, and component of replicase; ATPase & helices (C-terminal domain)
NS4A: Component of replicase, may recruit NS1 and other proteins into VRC
NS4B: Associates with membranes; may translocate to nucleus
NS5: MTR domain (N-terminal domain) and RDRP (C-terminal domain)

40
Q

Explain the evolution of HCV treatment

A

No vaccines available to prevent HCV infections
Old treatment regimens relied on combinational therapy with interferon and ribavirin –> severe side effects that caused lack of compliance, and liver transplants are very expensive
Direct acting antiviral (DAA) drugs developed recently against viral protease and RNA polymerase –> Nucleoside analog RdRP inhibitor drugs offer high percentage of SVR, high efficacy, short treatment duration (12 wks), fewer side effects, high barrier against resistant mutations

41
Q

What is Sofosbuvir?

A

Most effective nucleoside analog inhibitor of RNA polymerase

42
Q

What is special about Sofosbuvir?

A

In 2007 and best DAA to treat HCV infections, the cure rate: 30-70%, depending on HCV genotypes
Approval for clinical use in 2013
Highly effective against multiple genotypes, with a strong barrier for resistant mutants, no obvious side effects, administered orally

43
Q

What is great about the DAA’s?

A

HCV infection can now be cured within a short treatment regimen of 12-24 weeks with high SVR

44
Q

What does the NS3/4A PIs DAA class do?

A

Blocks viral protease enzyme that enables HCV to replicate and survive

45
Q

What does the Nucleoside polymerase inhibitors DAA class do?

A

Directly target HCV to stop it from making copies of itself in the liver, attach onto RNA to block replication –> this is Sofosbuvir

46
Q

What does the Non Nucleoside polymerase inhibitors DAA class do?

A

Stop HCV from replication by inserting themselves into nascent viral RNA so that RNA replication is blocked

47
Q

What does the NS5A inhibitors DAA class do?

A

Block NS5A that HCV needs to reproduce and for various stages of infection

48
Q

Where did HCV come from?

A

Bats may have served as the ancient and natural host for ancestors of Hepacivirus and other related viruses

49
Q

What is the HCV virus replication cycle?

A

Attachment: E protein binds one or more receptors (possibly glycosaminoglycan)
Penetration: receptor-mediated endocytosis
Genome uncoating: low pH dependent membrane fusion with endoscope membrane
Protein synthesis: associates with ER
RNA synthesis: Small vesicles derived from ER
Assembly and release: on the cytoplasmic side of the ER. Bud into ER lumen, exit via exocytosis. Fusion of vesicular membrane with plasma membrane releases virions

50
Q

Explain infection with Dengue virus

A

Dengue virus is responsible for 390M infections annually, with three outcomes:
1) Dengue fever
2) Dengue hemorrhagic fever
3) Dengue shock syndrome
The second infection with a Dengue virus in a person who has previously been infected with a different serotype leads to higher viremia and worse outcomes of disease

51
Q

What is a proposed mechanism for a Dengue antibody-dependent enhancement?

A

Cross reactive antibodies present in patient due to earlier infection bind to virions of the new infecting serotype, assisting viral entry into large # of cells expressing receptors for Fc domain of IgG
Rather than providing partial immunity to second infection, pre-existing antibodies facilitate the virus to enter large numbers of cells during a new infection

52
Q

What are the three distinct types of virion morphologies for the flavivirus?

A

Flavivirus virion contains a lipid bilayer and envelope proteins also arranged with an icosahedral symmetry: Immature viral particles display spikes on virion surface:

1) Immature virion (in vesicle at neutral ph)
2) Passing through TGN (pH 6)
3) Mature virion (upon release from infected cell)

53
Q

Explain the homodimer of envelope proteins

A

Fusion peptide: hidden by domain III
Domain II: responsible for interaction to form E dimers
Domain III: Ig fold, binding to receptor (unknown)
Within endosome, low pH changes conformation of E protein, exposing fusion peptide, releasing core into cytoplasm

MICR 3330 Midterm (8 decks)

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